This proposal will focus on biochemical, molecular and cellular aspects of atherogenesis and inflammation, especially as it relates to signaling by the nuclear hormone receptors, PPARg, PPARd and LXR. A major hypothesis of this proposal is that PPAR/LXR target genes in the monocyte/macrophage are transcriptionally by ligands present in the oxLDL particle as well as by drugs such as the TZDs. We have previously identified the scavenger receptor CD36, LXRa and the reverse cholesterol transporter ABCA 1 as either direct or indirect PPAR target genes. Through these genes PPARg has the potential to both promote (CD36) or inhibit (LXR/ABCA1 atherogenic function. The goal of Specific Aim I is to investigate whether the anti-atherogenic effects of TZDs are dependent upon PPAR expression in macrophages. Currently, it is simply unknown whether TZDs principle action is in peripheral tissue or in the lesion. This will be approached by using PPARg null bone marrow in transplantation studies in LDLR-/- male mice. Coupled to this goal will be the use of cDNA microarrays to identify the critical set of target genes that respond to PPARg, both in vitro as well as in the lesion. In Specific Aim 2, we have a unique opportunity to characterize the role of PPARd in macrophage differentiation and inflammation. This is possible because we have recently generated a line of PPARd null mice and in addition, have been able to derive PPARd null ES cells. We will analyze the role of this receptor in macrophage differentiation and particular, we will explore the possibility that the anti-inflammatory effects of TZDs may be exerted through their ability to activate this receptor. In Specific Aim 3, we will expand on these observations by characterizing in detail the role of PPARd in lipid metabolism, macrophage gene expression and atherogenesis. By transplanting PPARd null bone marrow into the LDLR-/- mice, we will determine the specific contribution of PPARd expression in macrophage to the atherosclerotic process. Again, as PPARd is a ligand activated transcription factor this provides an ideal situation to characterize the set of genes that serve as targets for this receptor and its ligands. Together these studies will provide valuable new insight into the biochemical and molecular mechanisms that underlie broad aspects of macrophage function and in particular, the role of oxLDL, inflammation, and anti-diabetic drugs in both the promotion, maintenance, and potential treatment of the atherogenic lesion.